This invention relates to novel macrolide derivatives that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections and disorders related to bacterial infections, such as atherosclerosis and cancer, in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad sprectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention are bond-spectrum macrolide antibodies that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa.
The present invention relates to a compound of the formula: 
or the pharmaceutically acceptable salt thereof; wherein the dashed line between positions 10 and 11 represents an optional double bond;
a is 0 or 1;
R1 is hydrogen or (C1-C10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH and R7S(O)n wherein n is 0, 1 or 2 and R7 is (C1-C8)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C1-
C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R2 is hydrogen or a hydroxy protecting group;
R3 is amino, cyano, N3, R10NH, R10C(O)NH, R10NHC(O)NH, R10NHC(S)NH, R10NHNHC(O)NH, R10ONHC(O)NH, R10O, R10OC(O)NH, R10S(O)n, R10 phosphoramido, R10 sulfonamido, SH, R10S wherein n is defined above and R10 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents selected independently from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C8-C10)aryl or (C2-C9)heteroaryl; or R3 is R12R13N wherein R12 and R13 are each independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl (C1-C6)alkyl;
R4 is hydrogen, methyl optionally substituted by one to two nitro, cyano, R14C(O) and R14OC(O); or R4 is N3, R14O, R14NH, R14S wherein R14 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl,(C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2, wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl; or R4 is R15N(C1-C6)alkyl wherein R15 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl;
X is oxygen or NOR16 wherein R16 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2, wherein R8 and R9 are each independently hydrogen or (C1-C6)alkyl optionally substituted by (C6-C9)aryl or (C2-C9)heteroaryl;
R5 is hydrogen or methyl;
or R3 and R4 may be taken together with the carbons to which they are attached to form: 
wherein the dashed line, between the nitrogen and the variable W of formula II, represents an optional double bond;
W is Cxe2x95x90O, Cxe2x95x90S, SO2 or Cxe2x95x90NR10 wherein R10 is as defined above;
Y is oxygen, sulfur or NR17 wherein R17 is hydrogen, R19, R19O or R19NH wherein R19 is hydrogen, (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C5-C10)aryl or (C2-C9)heteroaryl;
R18 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R20R21N, R20C(O), R20C(O)O, R20OC(O), R20C(O)NH, R20NHC(O), R20R21NC(O), and R20CO2 wherein R20 and R21 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)acyl or (C5-C10)aryl; or (C2-C9)heteroaryl;
R6 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylthio(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R6 is (C3-C10)cycloalkyl or (C5-C10)cycloalkenyl optionally substituted by (C1-C6)alkyl or halo; or R6 is (C2-C8)heterocycloalkyl or (C2-C9)heteroaryl optionally substituted by (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C10)cycloalkyl, (C5-C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1-C6)alkoxy or halo;
with the proviso that at least one of R17 or R18 is hydrogen;
with the proviso that when the dashed line between positions 10 and 11 represents a double bond, R4 is hydrogen; and
with the proviso that when a is zero, R1 is hydrogen.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. It is understood that for cyclic moieties at least three carbon atoms are required in said alkyl group, and for said alkyl group to include a carbon-carbon double or triple bond at least two carbon atoms are required in said alkyl group.
The term xe2x80x9chydroxy protecting groupxe2x80x9d, as used herein, unless otherwise indicated, includes benzoyl, benzyl, (C1-C6)alkanoyl, ((C1-C3)alkyl)3silyl, and tert-butyldimethylsilyl groups, preferably an acetyl group. The alkanoyl group can be cleaved after its administration to function as a prodrug.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
(C2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon or a sp3 hybridized nitrogen heteroatom.
(C2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2-9)heterocycloalkyl rings is through a carbon atom or a sp3 hybridized nitrogen heteroatom.
The term xe2x80x9cacylxe2x80x9d, as used herein, unless otherwise indicated, includes a radical of the general formula RCO wherein R is alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and the terms xe2x80x9calkylxe2x80x9d or xe2x80x9carylxe2x80x9d are as defined above.
The positions of the macrolide derivatives of formula I are defined as follows: 
The compounds of this invention include all configurational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (em., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
Certain compounds of the present invention may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them.
The present invention includes the compounds of the present invention, and the pharmaceutically acceptable salts thereof, wherein one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
Preferred compounds of formula I include those wherein a is 1 and R1 is (C1-C10)alkyl.
Other preferred compounds of formula I include those wherein R2 is hydrogen.
Other preferred compounds of formula I include those wherein R3 is N3, R10NH, R10C(O), R10NHC(O)NH or R10NHNHC(O)NH.
Other preferred compounds of formula I include those wherein R4 is hydrogen, R14NH or R14S.
Other preferred compounds of formula I include those wherein R6 is ethyl.
Other preferred compounds of formula I include those wherein W is Cxe2x95x90O and Y is NR17.
More preferred compounds of formula I include those wherein a is 1; R1 is (C1-C10)alkyl; R2 is hydrogen; R3 is N3, R10NH, R10C(O), R10NHC(O)NH or R10NHNHC(O)NH; R4 is hydrogen, R14NH or R14S and R6 is ethyl.
More preferred compounds of formula I include those wherein a is 1; R1 is (C1-C10)alkyl; R2 is hydrogen; R3 and R4 are taken together with the carbons to which they are attached to form the compound of formula II; W is Cxe2x95x90O and Y is NR17.
Specific preferred compounds of formula I include the following:
11,12-Dideoxy-3-de((2,6-dideoxy-3--methyl-3-1-methyl-xcex1-L-ribohexopyranosyl)oxy)-6-O-methyl-12,11-(iminocarbonyl(2-(3-(4-quinolinyl)propyl)hydrazono))-3-oxoerythromycin;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-6-O-methyl-12-iminocarbonyl((4-(4-(3-pyridinyl)-1H-imidazol-1-yl)butylimino))-3-oxoerythromycin;
11,12-Dideoxy-11,12-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyrano-5yl)oxy-6-O-methyl-10-iminocarbonyl((4-(4-(3-pyridinyl)-1H-imidazol-1-yl)butylimino))-3-oxoerythromycin;
11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)-oxy)-6-O-methyl-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2xe2x80x2-acetate;
11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)-oxy)-6-O-methyl-8-epi-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-12-xcex2-azido-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-rihexopyranosyl)oxy)-12-xcex2-azido-6-O-methyl-3-oxo-8-epierythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-12-xcex2-amino-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-12-xcex2-amino-6-O-methyl-3-oxo-8-erythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)ox)-12-xcex2-acetamino-6-O-methyl-3-oxoerythromycin-2xe2x80x2acetate;
11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-10-xcex2-azido-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-10-xcex2-amino-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-10-xcex2-acetamino-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(iminocarbonylhydrazono)erythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-10-xcex2-iminocarbonylhydrazono-6-O-methyl-3-oxo-erythromycin-2xe2x80x2-acetate;
11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-12-xcex2-isothiocyanato-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11,Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-12-xcex2-propagyloxy-6-O-methyl-3-oxoerythromycin-2xe2x80x2-acetate;
11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-6-O-methyl-11-nitromethyl-3-oxoerythromycin-1,2-enol-1,2-cyclicether-2xe2x80x2-acetate; and
11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3--methyl-3-O-methyl-xcex1-L-ribohexopyranosyl)oxy)-6-O-methyl-11-nitromethyl-8-epi-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2xe2x80x2-acetate.
The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, or disorder related to a bacterial infection or protozoal infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, or disorder related to a bacterial infection or protozoal infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention also relates to a pharmaceutical composition for the treatment of cancer, in particular non-small cell lung cancer, in a mammal, in particular a human, which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating cancer, in particular non-small cell lung cancer, in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
As used herein, unless otherwise indicated, the terms or phrases xe2x80x9cbacterial infection(s)xe2x80x9d, xe2x80x9cprotozoal infection(s)xe2x80x9d, and xe2x80x9cdisorder related to a bacterial infection or protozoal infectionxe2x80x9d include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase-positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus saprophyticus or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Chlamydia pneumoniae. Bacterial infections and protozoal infections, and disorders related to such infections, which may be treated or prevented in animals include the following: bovine respiratory disease related to infection by P. haemolytica, P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related to infection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by A. pleuro., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodysinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by Moraxella bovis; cow premature abortion related to infection by protozoa (i.e. neosporium); urinary tract infection in dogs and cats related to infection by E coli; skin and soft tissue infections in dogs and cats related to infection by Staph. epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida; and dental or mouth infections in dogs and cats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Other bacterial infections and protozoal infections, and disorders related to such infections, which may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., xe2x80x9cThe Sanford Guide To Antimicrobial Therapy,xe2x80x9d 26th Edition, (Antimicrobial Therapy, Inc., 1996).
The present invention also relates to a compound of the formula 
or the pharmaceutically acceptable salt thereof; wherein the dashed line between positions 10 and 11 represents an optional double bond;
a is 0 or 1;
R1 is hydrogen or (C1-10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH and R7S(O)n wherein n is 0, 1 or 2 and R7 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R2 is hydrogen or a hydroxy protecting group;
R3 is N3, R10NH, R10C(O)NH, R10NHC(O)NH, R10NHC(S)NH, R10NHNHC(O)NH, R10ONHC(O)NH or R10OC(O)NH, wherein R10 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl; or R3 is R11(C2-C4)alkynyl wherein R11 is (C1-C6)alkyl, (C6-C10)alkyl(C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; or R3 is R12R13N wherein R12 and R13 are each independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl (C1-C6)alkyl;
X is oxygen or NOR16 wherein R16 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2, wherein R8 and R9 are each independently hydrogen or (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R5 is hydrogen or methyl; and
R6 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylthio(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R6 is (C3-C10,)cycloalkyl or (C5-C10)cycloalkenyl optionally substituted by (C1-C6)alkyl or halo; or R6 is (C2-C8)heterocycloalkyl or (C2-C9)heteroaryl optionally substituted by (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C10)cycloalkyl, (C5-C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1-C6)alkoxy or halo;
with the proviso that when a is zero, R1 is hydrogen.
The present invention also relates to a compound of the formula: 
a is 0 or 1;
R1 is hydrogen or (C1-C10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH and R7S(O), wherein n is 0, 1 or 2 and R7 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R2 is hydrogen or a hydroxy protecting group;
R3 is NH2, N3, Oxe2x95x90Cxe2x95x90N or Sxe2x95x90Cxe2x95x90N;
X is oxygen or NOR16 wherein R16 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-C10)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2, wherein R8 and R9 are each independently hydrogen or (C1-C6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R5 is hydrogen or methyl; and
R6 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylthio(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three hydroxy or halo groups; or R6 is (C3-C10)cycloalkyl or (C5-C10)cycloalkenyl optionally substituted by (C1-C6)alkyl or halo; or R6 is (C2-C8)heterocycloalkyl (C2-C9)heteroaryl optionally substituted by (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C10)cycloalkyl, (C5-C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1-C6)alkoxy or halo.
The present invention also relates to an intermediate compound of the formula: 
a is 0 or 1;
R1 is hydrogen or (C1-C10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH and R7S(O)n wherein n is 0, 1 or 2 and R7 is (C1-C6)alkyl, (C2-C12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-C9)heteroaryl(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-10)aryl, (C2-9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R10C(O)2 wherein R8 and R9 are each independently hydrogen, (C1-6)alkyl optionally substituted by (C6-10)aryl or (C2-C9)heteroaryl;
R2 is hydrogen or a hydroxy protecting group;
R3 is NH2 or N3;
X is oxygen or NOR16 wherein R16 is (C1-6)alkyl, (C2-12)alkenyl, (C2-C12)alkynyl, (C3-C10)cycloalkyl(C1-6)alkyl, (C2-9)heterocycloalkyl(C1-6)alkyl, (C6-C10)aryl(C1-6)alkyl or C2-C9)heteroaryl(C1-6)alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-10,)aryl, (C2-C9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2, wherein R8 and R9 are each independently hydrogen or (C1-6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R5 is hydrogen or methyl; and
R6 is hydrogen, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C1-C6)alkoxy(C1-6)alkyl or (C1-C6)alkylthio(C1-C6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R6 is (C3-C10)cycloalkyl or (C5-C10)cycloalkenyl optionally substituted by (C1-C6)alkyl or halo; or R6 is (C2-8)heterocycloalkyl or (C2-9)heteroaryl optionally substituted by (C1-6)alkyl, (C2-8)alkenyl, (C2-C8)alkynyl, (C3-C10)cycloalkyl, (C5-C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1-6)alkoxy or halo.
The present invention also relates to a compound of the formula 
a is 0 or 1;
R1 is hydrogen or (C1-10)alkyl optionally substituted by fluoro, cyano, R7, R7O2C, R7C(O)NH and R7S(O)n wherein n is 0, 1 or 2 and R7 is (C1-6)alkyl, (C2-C12(C3-C10)cycloalkyl(C1-6)alkyl, (C2-9)heterocycloalkyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl or (C2-9)heteroaryl(C1-6)alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C1-C3)alkoxy, hydroxy, nitro, cyano, (C6-10)aryl, (C2-9)heteroaryl, R8R9N, R8C(O), R8C(O)O, R8OC(O), R8C(O)NH, R8NHC(O), R8R9NC(O) and R8OC(O)2 wherein R8 and R9 are each independently hydrogen, (C1-6)alkyl optionally substituted by (C6-C10)aryl or (C2-C9)heteroaryl;
R2 is hydrogen or a hydroxy protecting group;
R5 is hydrogen or methyl; and
R6 is hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkylthio(C1C-6)alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R6 is (C3-C10)cycloalkyl or (C5-10)cycloalkenyl optionally substituted by (C1-C6)alkyl or halo; or R6 is (C2-C8)heterocycloalkyl or (C2-C9)heteroaryl optionally substituted by (C1-C6)alkyl, (C2-6)alkenyl, (C2-C8)alkynyl, (C3-C10)cycloalkyl, (C5-C10)cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C1-C6)alkoxy or halo.